Drugs for ameliorating postcibal hyperglycemia

ABSTRACT

It is mentioned to provide drugs for ameliorating postcibal hyperglycemia, drugs for inhibiting an increase in blood glucose level and pharmaceutical compositions for preventing or treating diabetes, each containing a pharmaceutically acceptable anion exchange resin typified by colestimide. Thus, it becomes possible to provide drugs clearly exhibiting an effect of inhibiting an increase in postcibal blood glucose level.

This application is a U.S. national stage of International ApplicationNo. PCT/JP02/07655 filed Jul. 29, 2002.

TECHNICAL FIELD

This invention relates to drugs for ameliorating postcibal hyperglycemiacontaining a pharmaceutically acceptable anion exchange resin.

BACKGROUND ART

With regard to an anion exchange resin known as a cholesterol-loweringagent typified by colestimide (trade name: cholebine by MitsubishiPharma Corporation)or colestyramine resin (Bristol-Myers Squibb Co.),there was a report on the lowering activity of the blood glucose levelafter the administration for a certain period of time so far. However,the clear effect has not been observed and the mode of action has notbeen elucidated. While acarbose (trade name: glucobay by Bayer Yakuhin,Ltd.) and voglibose (trade name: basen by Takada Chemical industries,Ltd.) were at present know as drugs for ameliorating postcibalhyperglycemia, these drugs have no insulin secreting effect. Further,these drugs exhibit relatively frequent adverse effect such asflatulence and increase of flatus. Moreover, compared to thenon-absorbable anion exchange resin typified by cholebine, theabove-mentioned glucobay has four contraindications and cautions areneeded to subject patients.

On the contrary, a pharmaceutically acceptable anion exchange resinwhich exhibits a clear inhibitory effect on the increase of postcibalblood glucose level in the study on the influence against the diurnalvariation of blood glucose level in hypercholesterolemia patientscomplicated by type II diabetes has not been reported so far as much asthe present inventor knows.

DISCLOSURE OF THE INVENTION

The purpose of the present invention is to drugs for amelioratingpostcibal hyperglycemia containing a pharmaceutically acceptable anionexchange resin.

As a result that the present inventor has made intensive investigationsto achieve the above problem, the present inventor has found thatcolestimide (2-methylimidazole-epichlorohydrin copolymer) known as acholesterol-lowering agent exhibited a clear effect of inhibiting anincrease in postcibal blood glucose level in the study on the influenceagainst the diurnal variation of blood glucose level inhypercholesterolemia patients complicated by type II diabetes and hascompleted the present invention.

Namely, the first gist of the present invention lies in a drug foramelioration postcibal hyperglycemia containing a pharmaceuticallyacceptable anion exchange resin, and a drug for inhibiting an increasein blood glucose level containing a pharmaceutically acceptable anionexchange resin.

As the second gist of the present invention, there includes apharmaceutical composition for preventing or treating diabetes eachcontaining a pharmaceutically acceptable anion exchange resin as anactive ingredient. The preferable example includes that the postcibalhyperglycemia is ameliorate; the increase in postcibal blood glucoselevel is inhibited; diabetes is type II diabetes; and the diabetes isdiabetes as a disease complication in patients with hyperchlolestemia.

In any gist as mentioned above, the pharmaceutically acceptable resin isselected from colestimide, colestyramine resin, colestipol, sevelamerhydrochloride and colesevelam hydrochloride, and the preferable exampleof the pharmaceutically acceptable resin includes an anion exchangeresin synthesized by a polymerization reaction of epichlorohydrinderivative with an amine. More preferable embodiments include theinvention wherein the pharmaceutically acceptable anion exchange resinis colestimide.

In any gist as mentioned above, the preferable embodiment includes thatthe sulfonylurea drugs are used simultaneously, separately orsequentially.

The third gist of the present invention includes a method forameliorating postcibal hyperglycemia using a pharmaceutically acceptableanion exchange resin, and a method for inhibiting the increase ofpostcibal blood glucose using a pharmaceutically acceptable anionexchange resin.

BRIEF DESCRIPTION OF THE INVENTION

FIG. 1 shows the diurnal variation of the blood glucose level of case 1in Example 1.

FIG. 2 shows the diurnal variation of the blood glucose level of case 2in Example 1.

FIG. 3 shows the diurnal variation of the blood glucose level of case 3in Example 1.

FIG. 4 shows the diurnal variation of the blood glucose level of case 4in Example 1.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will be explained in more detail.

According to the present invention, a pharmaceutically acceptable anionexchange resin is an anion exchange resin which can be administered as adrug. The substance is not particularly limited, so far that thesubstance exhibits the inhibitory effect against the increase of thepostcibal blood glucose level in the study of the diurnal variation ofthe blood glucose level of the patients administered said anion exchangeresin as shown in the following examples. One of the example includescolestimide (2-methylimidazole-epichlorohydrin copolymer) as the mostpreferable example. Colestimide has an irregularly assembled andcomplicated stereostructure, and is represented by the fundamentalstructure of the following formula (I) that is partially represented bythe following formula (II), and is obtained by the polymerizationreaction of an epichlorohydrin derivative with an amine typified by animidazole derivative, namely by the production method described inJapanese Patent Unexamined Publication (Kokai) No. 60-209523.

Examples of other preferable anion exchange resins includechlolestyramine resin as mentioned above and colestipol((chloromethyl)oxirane-addedN-(2-aminoethyl)-N′-[2-[(2-aminoethyl)amino]ethyl]-1,2-ethylenediaminepolymer), which are sold by Sigma Inc. The cholestyramine resin is astrongly basic anion exchange resin containing a quaternary ammoniumgroups added styrene-divinylbenzene copolymer, and its fundamentalstructure is represented by the following formula (III).

The fundamental structure of sevelamer hydrochloride is represented bythe following formula, and can be prepared by the method described inU.S. Pat. No. 5,496,545 or a similar method thereto.

The fundamental structure of colesevelam hydrochloride is represented bythe following formula, and can be prepared by the method described inU.S. Pat. No. 5,607,669 or a similar method thereto.

In addition, anion exchange resins described in Japanese PatentPublication of International Application (Kohyo) Nos. 9-504782,9-500368, 10-501264, 10-501842, 11-507093, 11-512074, and 5-512332, andJapanese Patent Unexamined Publication (Kokai) Nos. 8-208750, 9-202732,10-114661, and 11-228449 can be used in the present invention, as longas they are not beyond the gist of the present invention.

The above compound itself, an active ingredient, can be used as drugsfor ameliorating postcibal hyperglycemia. It is preferably that apharmaceutical composition containing the above active ingredient ismanufactured by using an additive for a pharmaceutical preparation usedwidely, and then uses the same.

Such pharmaceutical compositions include tablets, capsules, finegranules, pills, troches and liquids, and the are orally administered (asublingual administration may be included).

The pharmaceutical composition for oral administration can bemanufactured by a conventional method used widely, such as mixing,filling or compressing. Further, by applying repeated formulationprocedures, the active ingredient may be distributed in a pharmaceuticalcomposition containing a large amount of the excipient. For example,tablets or capsules used for the oral administration are preferablyprovided as unit dosage forms, and they may contain carriers for thepharmaceutical preparations used conventionally, such as binder, afilling material, a diluent, a compressing agent, a lubricant, adisintegrator, a coloring agent, a flavoring agent, and a moisteningagent. A tablet may be manufactured, for example, as a coated tabletaccording to a well-know method in the art by using a coating agent.

Examples of the preferably filling material include cellulose, mannitol,lactose or the like. Starch, polyvinylpyrrolidone, a starch derivativesuch as sodium starch glycolate or the like as a disintegrator, andsodium lauryl sulfate or the like as a lubricant can be used asadditives for the pharmaceutical preparation. A pharmaceuticalcomposition in the form of a liquid for oral administration is providedas, for example, a pharmaceutical composition such as an aqueous or oilysuspension, a solution, an emulsion, a syrup or an elixir; or a drypharmaceutical composition which can be re-dissolved in water or anappropriate medium before use.

In the liquids, additives commonly used may be added such as, forexample, a precipitating preventing agent such as sorbitol, syrup,methyl cellulose, gelatin, hydroxyethylcellulose,carboxymethylcellulose, aluminum stearate gel or hydrogenated ediblefat; an emulsifier such as lecithin, sorbitan monooleate or acacia; anoily ester such as almond oil, refined coconut oil or a glycerin ester;a non-aqueous medium such as propylene glycol or ethyl alcohol (edibleoil may be included); a preservative such as methyl ester, ethyl esteror propyl ester or p-hydroxybenzoic acid, or sorbic acid; and, ifnecessary, a conventionally flavoring agent or coloring agent.

The above pharmaceutical composition or oral administration such as inthe form of tablets, capsules, fine granules or the like generallycontain 5 to 95% by weight, preferably 25 to 90% by weight of the activeingredient.

Colestimide has been sold by Mitsubishi Pharma Corporation as a tradename of “cholebine”, and cholebine, per se, can be used for the presentinvention.

Dose of the drugs for ameliorating postcibal hyperglycemia of thepresent invention may appropriately determined depending upon the activeingredient use, the age, health conditions, body weight of the patient,severity of the disease, a type and frequency of the simultaneoustherapy or treatment, a nature of the desired effects and the like. Ingeneral, daily dose for the adult may range 1 to 60 g as a weight of theactive ingredient, and the drugs may be administered once or severaltimes a day.

In the present invention, the above pharmaceutically acceptable anionexchange resin and a sulfonylurea drug may be used simultaneously,separately or sequentially. Described specifically, a drug containingthe above anion exchange resin as an effective ingredient and asulfonylurea drug maybe be administered as one pharmaceuticalcomposition or as respective pharmaceutical compositions, based on thedose adjusted, depending on the age, condition, sex, symptoms, or thelike of a patient as needed. In the latter case, they may beadministered simultaneously in the same dosage form or different dosageforms; administered sequentially on the same day in the same dosage formor different dosage forms; or administered at regular intervals forseveral days, several weeks or several months, depending on the age,condition, sex, symptoms or the like of a patient.

The sulfonylurea drugs are not specifically limited and, in more detail,include the drugs exhibiting the inhibitory effect against the increaseof blood glucose level as shown in the example hereinafter, and, forexample, tolbutamide (trade name: diabetose/Nippon Iyakuhin Kogyo K.K.,Diaben/Chugai Pharmaceutical Co., Ltd.), glimepiride (trade name:amaryl/Aventis Pharma), gliclazide (trade name: glimicron/DianipponPharmaceutical Co., Ltd.), and glibenclamide (trade name:euglucon/Nippon Roche, Yamanouchi Pharmaceutical Co. Ltd.) areexemplified. As these sulfonylurea drugs, the already marketed reagentsor drugs can be used.

EXAMPLE

The present invention will be explained according to the followingexamples in more detail. It should however be borne in mind that thepresent invention is not limited by them. Colestimide used in thefollowing examples is 70% cholebine granule which is sold by MitsubishiPharma Corporation.

Example 1

(Subject and Method)

Influences of colestimide administration on the diurnal variations ofserum lipid level and blood glucose level were investigated before andafter administration in the same case by using, as subjects, inpatients(adults, either female or male) who had suffered fromhypercholesterolemia complicated by type 2 diabetes, and whose calorieintake had been controlled strictly and blood lipid level and bloodglucose level had been grasped.

The diurnal variations of blood glucose level were measured at ten timepoints in total. They were “before breakfast (at 8:00), two hours afterbreakfast (at 10:00), before lunch (at 12:00), two hours after lunch (at14:00), before dinner (at 18:00), two hours after dinner (at 20:00), at0:00, at 3:00, at 6:00 and at 8:00 in the next morning”.

The test was performed in accordance with the following schedule:

-   (1) Period of observation: 2 weeks after hospital stay is started

In the period of observation, it was confirmed that the patients hadmaintained stable serum lipid level, serum glucose level, body weightand the like.

-   (2) Period of treatment: two weeks after the administration of    colestimide was started.

The diurnal variation of serum lipid level and blood glucose level ofthe patients under administration with colestimide for 2 weeks werecompared with those of the patients in the period of observation.

(Test Drug, Administration Manner and Amount)

Colestimide was administered before breakfast and before lunch, that is,twice a day, each 1.5 g.

(Diet Therapy and Drugs Used in Combination)

Throughout the periods of observation and treatment, the caloric intakewas fixed (25 to 30 kcal per kg of a standard weight). Whenanti-hyperlipidemia drugs other than colestimide (such as an HMG-CoAreductase inhibitor, a fibrate drug, probucol (generic name, “Lorelco”,trade name; product of Otsuka Pharmaceutical Co., Ltd.), and“Sinlestal”(product of Daichi Pharmaceutical Co.; Ltd.)) had still beenadministered, their administration was continued without changing theadministration manner and amount throughout the periods of observationand treatment and additional administration the periods of observationand treatment and an influence on the serum lipid level wereadministered without changing the administration manner and amountthroughout the periods of observation and treatment, while drugs whichmight have an influence on the blood glucose level (such as anα-glucosidase inhibitor and an insulin resistance improver) were notadministered in principle. when a sulfonylurea drug had already beenadministered, however, its administration was continued without changingthe administration manner and amount throughout the periods ofobservation and treatment. Also, the other drugs possible throughout theperiods of observation and treatment.

(Results)

Details of the subjects and results of the therapy will next bedescribed. In the following data, TC means the total cholesterol level,HDL-C means the HDL-cholesterol level, and TG means the triglyceridelevel. The numbers before and after the arrow are their levels beforeand after colestimide administration, each in unit of mg/dL. In all thegraphs, ? shows the blood glucose level before colestimideadministration and ? shows the blood glucose level after colestimideadministration. Time points (blood collection time) are plotted on theabscissa, while the blood glucose level (mg/dL) is plotted on theordinate.

-   Case 1: 75-year old male administered with tolbutamide (generic    name; 500 mg/day)    -   TC: 210 ? 152, TG: 74 ? 75    -   The diurnal variations of his blood glucose level are shown in        FIG. 1.-   Case 2: 63-year old male subjected to only diet therapy    -   TC: 204 ? 142, HDL-C: 38 ? 33, TG: 221 ? 146    -   The diurnal variations of his blood glucose level are shown in        FIG. 2.-   Case 3: 78-year old male subjected to only diet therapy    -   TC: 188 ? 155, HDL-C: 44 ? 40, TC: 176 ? 168    -   The diurnal variations of his blood glucose level are shown in        FIG. 3.-   Case 4: 73-year old male administered with glimepiride (generic    name; 1 mg/day)    -   TC: 242 ? 198, HDL-C: 66 ? 66, TG: 100 ? 84    -   The diurnal variations of his blood glucose level are shown in        FIG. 4.

It is apparent from the results of Case 2 and Case 3 that singleadministration of colestimide is effective for inhibiting a postcibalincrease in the blood glucose level, and from the results of Case 1 andCase 4 that use of colestimide and a sulfonylurea drug in combination isalso effective for inhibiting a postcibal increase in the blood glucoselevel.

INDUSTRIAL APPLICABILITY

According to the present invention, drugs which clearly exhibit theinhibitory effect on the postcibal blood glucose level are obtained.Further, the drugs of the present invention with the combination of thesulfonylurea drugs show the inhibitory effect on the postcibal bloodglucose level.

The present application was filed with claiming the conventionalpriority based on Japanese Patent Application No. 2001-229097. All ofthe patent bulletins, patent publication (Kokai) bulletins, literaturescited in eth specification can be used alone or in combination thereofas the references of the present invention.

1. A method for ameliorating postcibal hyperglycemia consisting ofadministering a therapeutically effective amount of colestimide as theactive ingredient to a patient in need thereof.
 2. A method forinhibiting an increase in postcibal blood glucose level, consisting ofadministering a therapeutically effective amount of colestimide as theactive ingredient to a patient in need thereof.